Project Summary The candidate applies a R03 grant that will expand his K01 supported career development in clinical research to complement his multidisciplinary training in immunology, microbiology, genetics and epidemiology and enable him to advance his scientific career by investigating the role of the gut mycobiome in Crohn's disease (CD) under the influence of major genetic risks. CD is an inflammatory bowel disease (IBD) resulting from defects in the mucosal immune response to enteric bacteria/fungi in genetically susceptible individuals. Over 160 susceptibility loci, particularly immune response genes such as CARD9, NOD2/CARD15, IRGM and ATG16L1, have been associated with CD risk in individuals of European ancestry. Previous studies have established the distinct membership and abundance of the gut mycobiota in CD patients compared with healthy controls, inferring a possible role of the gut mycobiome in CD pathogenesis. Accumulating evidence supports the role of the major CD susceptibility genes, CARD9 in the processing of fungal antigens and innate immunity. However, it is unclear whether carriage of the major genetic risk alleles correlates with an abundance of any particular fungi species in the gut. In this study we will investigate whether fungi profile differs between carriers and non-carriers of the major CD susceptibility alleles while focusing on a genetically homogeneous Ashkenazi Jewish (AJ) population, who has the highest prevalence of CD comparing with other ethnic/racial groups. The hypothesizes include: 1) the fungi profile of the gut is moderated by the carriage of CARD9 or CLEC7A risk variants and 2) the CD risk in the AJ population is attributable to the unique combination of fungi species in the gut and host genetics. To test these hypotheses, the candidate will reuse the K01 supported recruited samples from AJ CD patients enrolled in an ongoing registry of patients with IBD in the Division of Gastroenterology at The Mount Sinai School of Medicine, New York and already genotyped for the major CD risks. The candidate will also reuse the AJ controls without CD recruited from the Mount Sinai Biobank for the K01 study. We will utilize Fungal ITS2 targeted-amplicon pair-end deep sequencing technique followed by bioinformatics and statistical approaches to characterize the gut mycobiota in study subjects with regard to disease status and genetic risks. By studying a more genetically homogeneous population (AJ), combining the microbiome data from the K01 study, this R03 study will attempt to gain a better understanding of the microbiome-mycobiome-host gene interaction associated with disease pathogenesis. This can help build comprehensive diagnostic tools to identify individuals at risk of developing CD, as well as develop novel personalized treatments for AJ CD patients. In addition, this project will help to establish a strong multidisciplinary foundation for the candidate's future career in translational research.